Anxiety disorders are typically characterized by an exaggerated, recurrent or inappropriate apprehension, uncertainty, anxiety, or fear. They are classified according to the severity and duration of their symptoms and specific affective characteristics. Some categories are: (1) generalized anxiety disorder (GAD); (2) obsessive-compulsive disorder (OCD); (3) panic disorder; (4) post traumatic stress disorder (PTSD); (5) social anxiety disorder (social phobia); (6) specific phobia; and (7) separation anxiety disorder. Current treatment for most anxiety disorders may involve a combination of psyco-social treatment with antidepressant medication. Psycho-social treatments used in the treatment of anxiety disorders include, for example, cognitive behavioral therapy (CBT), exposure therapy, anxiety management and relaxation therapies, or psychotherapy. Drugs used to treat anxiety disorders include, for example, selective serotonin reuptake inhibitors (SSRIs), tricyclic antidepressants, benzodiazepines, beta blockers, or monoamine oxidase inhibitors (MAOIs).
Anxiety disorders may develop from a complex set of risk factors, including genetics, brain chemistry, personality, and life events. A combination of factors may underlie a given anxiety disorder. For example, while trauma itself acts as a trigger for post traumatic stress disorder, genetic factors may predispose some individuals toward being more or less susceptible to developing the full-blown disorder. Genetic factors have been suggested to play a role in several other anxiety disorders, including for example, obsessive-compulsive disorder (OCD).
OCD is a neuropsychiatric condition affecting an estimated 1 to 3% of the population worldwide. It is associated with significant morbidity, as reflected in its ranking by the World Health Organization as one of the 10 most disabling medical conditions. Large, controlled family studies have indicated significant familial aggregation of OCD, with a meta-analysis indicating an aggregate risk of 8.3% compared with the general population prevalence of approximately 2%, resulting in an odds ratio of 4 for first degree relatives of OCD probands. Twin studies in OCD suggest increased concordance in monozygotic twin pairs (80-87%) compared with dizygotic twin pairs (47-50%). Taken together, the family studies and twin studies indicate that genetic determinants may play a significant role in the etiology of OCD.
Molecular genetic studies in OCD have been largely based on a candidate gene approach, in which variants (polymorphisms) of candidate genes are genotyped in a population of affected probands and either population or family-based controls. Candidate genes may be selected based either on location within a linkage region identified in a whole genome scan, or the presumed role of the gene in pathogenesis. In the only published genome scan based on OCD probands, a region of suggestive linkage (LOD=2.25) was found in chromosome 9p24 based on seven multigenerational large pedigrees in which there was a pediatric proband with OCD (Hanna G L, Veenstra-VanderWeele J, Cox N.J. et al. Genome-wide linkage analysis of families with obsessive-compulsive disorder ascertained through pediatric probands. Am J Med Genet 2002;114:541-52), a linkage finding which was subsequently replicated in a study by Willour and colleagues (Willour V L, Yao Shugart Y, Samuels J et al. Replication study supports evidence for linkage to 9p24 in obsessive-compulsive disorder. Am J Hum Genet 2004;75:508-13).
Within the 9p24 region of 7.5 MB only one gene has been shown to be expressed in brain, the neuronal glutamate transporter gene SLC1A1 (OMIM #133550), which codes for the neuronal glutamate transporter excitatory amino acid carrier 1 (EAAT3/EAAC1). This gene is highly expressed within cerebral cortex, striatum, and thalamus, brain regions which are connected in functional cortico-striatal-thalamic circuits (CSTC's) implicated in OCD (Bronstein Y, Cummings J. Neurochemistry of frontal-subcortical circuits. In: Lichter D, Cummings J, eds. Frontal-subcortical circuits in psychiatric and neurological disorders. New York: Guilford Press; 2001:59-91).
SLC1A1 is a strong functional candidate gene for OCD given the mounting evidence for a role of altered glutamate neurotransmission within CSTC's in the pathogenesis of OCD. However, genetic association studies between OCD and SLC1A1 and the surrounding genetic region have produced mixed findings. Veenstra-Vanderweele and colleagues (Veenstra-VanderWeele J, Kim S J, Gonen D, Hanna G L, Leventhal B L, Cook E H, Jr. Genomic organization of the SLC1A1/EAAC1 gene and mutation screening in early-onset obsessive-compulsive disorder. Mol Psychiatry 2001;6:160-7) failed to find any evidence for biased transmission in a family-based association analysis of a haplotype consisting of two intronic SNPs in intron 3 of SLC1A1 (p=0.42). Willour and colleagues (Willour et al, supra.) found modest associations between two microsatellite markers flanking SLC1A1, GATA62F03 (p=0.02) and D9S288 (p=0.05). Accordingly, association between SLC1A1 and OCD is still not clear.
Similarly, genetic markers for other anxiety disorders have yet to be clearly established.
According to the Anxiety Disorders Association of America (ADAA; www.adaa.org) anxiety disorders may be the most common psychiatric illnesses affecting both children and adults. 19 million adult Americans are estimated suffer from anxiety disorders. However, only about one-third of those suffering from an anxiety disorder are properly diagnosed and receive treatment.
Accordingly, there is a need for diagnostics or treatments pertaining to anxiety disorders. Furthermore, there is a need to further clarify an association between anxiety disorders and SCLA1A or SCLA1A variants.